The present invention refers to the use in human and veterinary medicine of some 2,4-disubstituted phenol derivatives that, due to their surprisingly high 5-lipoxygenase inhibiting activity and to their low toxicity, are specially useful for the preparation of medicaments for the treatment of the numerous leukotriene-mediated diseases.
Cyclooxygenase inhibitors have been used in therapy for a long time, specially those referred to as non-steroidal antiinflammatory agents, such as aspirin, indomethacin, ibuprofen or piroxicam. It is known today that these products, by inhibiting the cyclooxygenase enzyme, prevent or make difficult the conversion of arachidonic acid into prostaglandins and thromboxanes. Unfortunately, the majority of these antiinflammatory agents present more or less severe adverse side effects, mostly of gastrointestinal type; therefore the research for new products with antiinflammatory activity still goes on.
Recently it has been found that 5-lipoxygenase (5-LO in the following) is an essential enzyme for the conversion of arachidonic acid into leukotrienes, and the later compounds and their metabolites play an important role in the genesis and development of numerous diseases. In the biomedical literature of the last years there are hundreds of publications which, with more or less evidence, associate leukotrienes with various diseases, including the following: musculoskeletal and inflammated joints diseases (rheumatoid arthritis, ostheoarthritis, juvenile arthritis, gout, arthrosis, discoespondilitis, bursitis, tendinitis, equine cauda . . . ); inflammatory diseases of the gastrointestinal tract (ulcerative colitis, Crohn disease, gastritis, chronic intestinal disease, rectitis, linphoplasmocitary enteritis . . . ); diseases involving inflammation of the respiratory tract (asthma, dyspnea, bronchitis, allergic rhinitis, adult respiratory distress syndrome . . . ); septic shock and shocks attributable to trauma, to ischemia of the gastrointestinal tract, to hemorrhage or to endotoxin; inflammatory diseases of the skin (psoriasis, eczema, dermatitis, leishmaniosis . . . ), diseases involving ocular inflammation (idiopathic keratitis, dry keratoconjuntivitis . . . ), as well as diseases attributable to allergies or hypersensitivity. The full knowledge of the mechanism of action of the leukotrienes and their metabolites is not yet fully known, and new therapeutic applications for 5-LO inhibitors are constantly being discovered. For example, as they substantially influence the organism, in some cases 5-LO inhibitors improve the defense mechanisms against the development or reoccurrence (metastasis) of cancerous tumors, or against the development of diseases involving microorganisms; therefore it is not surprising that the activity of 5-LO inhibitors is observed symptomatically in vivo but not in vitro.
The therapeutic interest in 5-LO inhibitors is quite high mainly because many of the diseases in which they are potentially useful still do not have satisfactory treatments. This is the case, for example, of asthma, psoriasis, ulcerative colitis, osteoarthritis or herpes, diseases which chronically affect a large part of the population and which still do not have a satisfactory therapy.
As a consequence of the previously stated, in the last years numerous pharmaceutical companies have been interested in the research and development of drugs with 5-LO inhibiting activity, as illustrated by dozens of patent applications published on the subject, and by the fact that more than 30 products with this activity appear in the databases on pharmaceutical products under development. However it is highly significant that, despite the high therapeutical interest of products with this activity, and despite the great efforts placed on their research and development, no satisfactory 5-LO inhibitor agent has reached the market yet, with the exception of ketaconozale and related products. This fact clearly indicates that there is a high difficulty involved in the development of such a product, what can be due to some of the following reasons: Some products, such as nordihydroguayaretic acid (NDGA), are very active but not enough specific (NDGA is a potent 5-LO inhibitor, but it is also inhibitor of all dioxygenases, and therefore cannot be used therapeutically). Other products, such as benoxaprofen and lonapalene, although they have been developed as 5-LO inhibitors, in practice they have turned out to be much too toxic (for this reason benoxaprofen was withdrawn, after having been commercialized). Others products, such as ketaconozale, although they have an acceptable toxical degree for an sporadic administration (in fact ketaconozale is being used as a fungicide), they are not acceptable for a chronic administration. Finally, other products have proved not to be active enough. Summarizing, there is no a good solution yet to the problem of having products that, showing a good 5-LO inhibiting activity, are little toxic and pharmaceutically viable.
The present invention provides a group of such products, all of which are derivatives of 2,4-disubstituted phenols, thus satisfactorily solving the above-mentioned problem. Several products of the present invention are chemically known in the literature, while others are completely new, although easy to prepare from available reactants. In either case, their 5-LO inhibiting activity has not been previously disclosed, and nothing in the previous art makes this activity obvious.
Patents EP 190.683, EP 235.575 and EP 372.409 mention 5-LO inhibiting activity for some 2,6-di-tert-butyl and 2,6-diphenyl phenol derivatives which are not included in the present invention. Patent EP 334.119 discloses as 5-LO inhibitors a group of phenols with a substituted vinyl radical at position 4, not included either in this invention. European patent application EP 147.892 mentions certain analgesic and antiinflammatory activity for a product which is included in the present invention, namely the 2,4,6-triiodophenol. But in this patent no specific leukotriene-mediated disease is mentioned (nothing is said, for instance, about asthma, psoriasis or ulcerative colitis); besides, the comparative tests disclosed in EP 147.892 were done against typical inhibitors of cyclooxygenase, such as indomethacin and aspirin. Therefore this document could suggest to an expert that 2,4,6-triiodophenol has some cyclooxygenase inhibiting activity (what is actually true and easily checked), this activity being typical of common analgesics and non-steroidal antiinflammatory agents. But nothing in that patent or in the common general knowledge teaches or makes obvious that 2,4,6-triiodophenol has one of the highest 5-Lo inhibiting activity ever disclosed. Such a teaching is part the present invention.